Tobacco smoking prevalence among the HIV-positive population is approximately 50%-70%, which is 2 to 3 times higher than that in non-HIV population (Centers for Disease Control and Prevention, 2005). Nicotine (NIC), the primary reinforcing agent in tobacco, stimulates the mesolimbic dopamine (DA) system through activation of nicotinic acetylcholine receptors (nAChRs) in the brain. The DA projection from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) plays a critical role in NIC-mediated behaviors that may contribute to NIC craving in humans. Compared to non-HIV individuals, HIV-positive smokers are more likely to develop NIC dependence, suffer from depression and experience more difficulty to quit smoking. Taken together, tobacco smoking presents an elevated health hazard to HIV-positive individuals, and HIV infection may increase the risk of NIC dependence. Currently, little is known about the neurobehavioral mechanisms through which HIV-positive individuals show increased vulnerability to NIC dependence. Infection with HIV is associated with a variety of neurological impairments that result from the presence of the viral proteins. HIV-1 trans-activator of transcription (Tat) protein is essential for efficient viral replication and plays a crucial role in pathogenesis of HIV-1-associated dementia and synergistic neurotoxicity in the dopaminergic system. Our recent studies indicate that intra-striatal infusion of Tat decreases K+evoked DA levels in rats (Ferris et al., 2008) and that intra-accumbal Tat alters the acute and sensitized response to cocaine (Harrod et al., 2008). The preliminary results show that in vitro exposure to the Tat protein decreases DA transporter (DAT) function in rat striatum. Thus, the major experimental question of this proposal is: Does microinjection of Tat into either the NAc or VTA produce neural changes that alter sensitivity to acute and/or repeated intravenous (IV) NIC administration? The proposed research will test the following hypothesis: HIV-1 Tat protein alters functioning of the mesolimbic dopamine system, thereby resulting in NIC-mediated behavioral changes. The experiments proposed here are designed to focus on two specific aims: 1) To determine the effects of microinjected Tat on IV NIC-mediated locomotor sensitization, 2) To determine the effects of microinjected Tat on DAT activity and nAChRs expression in rats with acute or repeated IV NIC administration. The long-term experimental goal of the present research proposal will be to elucidate the underlying neurobiological mechanisms of Tat-induced dysfunction of mesolimbic DA system contributing to NIC dependence. Such research will provide new insights into developing effective smoking cessation programs in HIV-positive population. PUBLIC HEALTH RELEVANCE: These results will provide new insights into the underlying neurobehavioral mechanisms through which HIV- positive individuals show increased vulnerability to NIC dependence. Understanding this mechanism will have the potential to facilitate the development of effective smoking cessation programs in HIV-positive population.